DPP-IV is a serine protease, which recognizes an amino acid sequence having proline (or alanine or hydroxyproline) the penultimate position from the N-terminal and produces dipeptide Xaa-Pro (Xaa shows an optional amino acid and Pro shows L-proline). DPP-IV is widely distributed in mammalian tissues and is known to be present particularly in blood, kidney, intestinal epithelium and placenta.
While the physiological role of DPP-IV in mammal has not been completely elucidated, its involvement in a broad range of functions of living organisms such as degradation of neuropeptide [Heymann et al., FEBS Letters vol. 91, 360–364 (1978)], activation of T cell [Schon et al., Biomedica Biochimica Acta vol. 44, K9–K15 (1985)], adhesion of metastatic tumor cell to endothelium [Johnson et al., Journal of Cell Biology, vol. 121, 1423–1432 (1993)], invasion of HIV virus into lymphocytes [Callebaut et al., Science vol. 262, 2045–2050 (1993)] and the like is being clarified. Of these, the role of DPP-IV as an enzyme that inactivates glucagon-like peptide (GLP-1), which is a biogenic substance having a strong insulin secretion ability and controls postprandial blood glucose level, has been drawing attention [Deacon et al., Journal of Clinical Endocrinology and Metabolism, vol. 80, 952–957 (1995)].
GLP-1 is known to be metabolized in several minutes in a living organism. In the metabolism, that by DPP-IV is particularly important, because it quickly cleaves GLP-1 and produces inert GLP-1 [Deacon et al., American Journal of Physiology, vol. 271, E458–E464 (1996)]. In addition, it is considered that physiological action of GLP-1 becomes attenuated further because this inert GLP-1 shows an antagonistic action on GLP-1 receptor [Knudsen et al., European Journal of Pharmacology, vol. 318, 429–435 (1996)]. Therefore, a method for suppressing cleavage of GLP-1 by inhibition of DPP-IV is considered to be the most superior approach for reinforcing GLP-1 action. That is, a DPP-IV inhibitor is expected to be a superior treatment method of curing postprandial hyperglycemia without side effects, such as prolonged hypoglycemia and the like, for non insulin-dependent diabetic (type II diabetes) patients.
Patent applications relating to DPP-IV inhibitors include the following.
Japanese Patent Application under PCT laid-open under kohyo No. 9-509921 discloses (S)-2-cyano-1-L-prolinepyrrolidine derivative. The L-α-amino acid corresponding to the L-proline moiety of the compound disclosed therein characteristically has a lipophilic side chain.
In addition, WO99/61431 describes DPP-IV inhibitory activities of a compound consisting of natural amino acid and thiazolidine or pyrrolidine.